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The function and mechanism of aldh9a1b in diabetes

ABSTRACT: The function and mechanism of aldh9a1b in diabetes

PROVIDER: PRJNA925841 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23149200.fastq.gz	Fastqsanger.gz
	SRR23149188.fastq.gz	Fastqsanger.gz
	SRR23149189.fastq.gz	Fastqsanger.gz
	SRR23149190.fastq.gz	Fastqsanger.gz
	SRR23149191.fastq.gz	Fastqsanger.gz

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The function and mechanism of aldh9a1b in diabetes

Project description:Reactive aldehydes such as 4-HNE, MDA and acrolein are implicated in the pathological development of diabetes as their widespread and universally exposed characteristics. Trans, trans-2,4-decadienal (tt-DDE) come from lipid peroxidation of omega-6 and is most abundant aldehyde in cooking oil fumes, while, its role in diabetes remained unknown. Aldh9a1 is a cytosolic enzyme that catalyze the NAD+-dependent oxidation of a variety of aldehydes and has its homology aldh9a1b in zebrafish. To investigate the function of endogenous and exogenous tt-DDE, aldh9a1b knockout zebrafish are established using CRISPR/Cas9 technology. TT-DDE was confirmed to act as substrate for aldh9a1b and a series of experiments are performed on a histological, metabolomic and transcriptomic level in aldh9a1b-/- zebrafish. Both aldh9a1b-/- larvae and adult fish displayed abnormal retinal vasculature and impaired glucose homeostasis, which are caused by tt-DDE induced downregulated insulin signaling pathway. Furthermore, the abnormal hyaloid vasculature in the fish can be reversed by insulin receptor sensitizer and metformin exhibited strongest effects among them. Altogether, these results identified tt-DDE as the preferred substrate for aldh9a1b, which subsequently causes microvascular damage and impaired glucose metabolism by insulin resistance.

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Project description:Aims/hypothesis Pancreatic β cell dedifferentiation underlies the reversible reduction in β cell mass and function in diabetes. Interventional targets and adjuvant therapies to prevent/reverse β cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, while the underlying molecular mechanism remains elusive. Methods LDHA expression and activity were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on β cell function and identity was investigated in high-fat diet (HFD) feeding mice and db/db mice. ChIP-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on the H3K9la enhancement and beta cell function under glucotoxic conditions. Results We demonstrated that inhibition of LDHA effectively preserved β cell identity, which not only delay disease progression in prediabetic stage, but also improve insulin output and glucose homeostasis in diabetic models. Mechanistically, the activation of LDHA led to a marked increase in histone H3 lysine 9 lactylation (H3K9la) in the promoter region of the β cells dedifferentiation markers Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering β cell dedifferentiation as well as impaired glucose homeostasis and β cell function in mice. Conclusions/interpretation We unraveled the role of lactate dehydrogenase A (LDHA)-mediated metabolic and epigenetic reprogramming in β cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.

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